It is well established that a causal association exists between obesity associated diabetes and the increased risk for development of infectious disease. The exact mechanisms underlying the higher incidence of infection are not completely understood. However, certain components of the immune system may be compromised. The working hypothesis for this proposal is that immunologic function is altered in the genetically obese Zucker rat, an animal which has many characteristics of the maturity onset (Type II) diabetes in humans. Preliminary data indicate normal in vitro responsiveness to B and T-cell mitogens, but a significantly reduced cidal activity by macrophages from obese rats to Candida albicans. Reduced killing by macrophages may also reflect reduced antigen presentation and alterations in other aspects of macrophage reactiveness. This would have profound implications for effectiveness of the cell mediated immune response (CMI), which is dependent on macrophage - T cell interactions. Lean and obese rats will be compared to determine whether reduced macrophage cidal activity to C. albicans is reflected in increased susceptibility to infection. Rates of clearance from the blood, colonization in target organs and morphotype of Candida present will be compared. If necessary, alternative infectious agents will be assessed comparing rates of ingestion and killing by PMNs and macrophages to clearly identify a pathogen for which CMI is crucial for systemic elimination. The effects of hyperlipidemic serum from obese rats on killing of C. albicans by macrophages from lean and obese rats will be determined. CMI will be tested in vivo and in vitro. Changes in DTH responsiveness to Candida and BCG will be followed during infection in lean and obese rats. In vitro correlates of CMI will also be followed. Migration inhibitory factor, delta-interferon and interleukin-2 levels will be measured in serum from immune- stimulated lean and obese animals. These studies, taken together, will demonstrate the extent of immune compromise in obese Zucker rats and a clear indication of which aspects of CMI are most affected. This will provide a firm basis for future studies of immune function in an existing animal model which shows features in close correlation with human Type II diabetes.